The central goal of this proposal is to exploit the use of a new mutant murine strain to advance the understanding of autoimmune disorders. A new line of mice has been derived in which animals develop a severe generalized lymphadenopathy together with autoimmune glomerulonephritis and hyperimmunoglobulinemia. Significantly, the animals produce auto antibodies against double-stranded DNA and Sm antigen, both of which are specific markers for Systemic Lupus Erythematosus (SLE). Immune function studies showed a combination of severe lymphoid dysfunction and developmental defect not seen in other murine autoimmune disease models. The disease is passed with a Mendelian frequency consistent with a recessive mutation of an autosomal gene. Therefore, the disease arose from a spontaneous mutation of a gene which we have named lag (lymphoproliferative autoimmune glomerulonephropathy). Using chromosomal satellite markers to scan the murine genome, preliminary data indicate that a putative locus for the lag gene is the telomeric end of chromosome 2. This is not a region that has been linked before to autoimmune disease. The goal of this proposal is to exploit this remarkable new murine model to learn about autoimmune disease. In Specific Aim 1, we will map the location of the gene and identify the lag gene by combining positional cloning with a candidate gene approach. In Aim 2 we will characterize the disease process for the lag phenotype and identify the cells causing the disease. In Aim 3 we will examine in detail the effect of the lag mutation on T cell development. In Aim 4 we will investigate how the lag mutation affects T cell function. To support these studies, various TCRxlag transgenic animals will be generated to help the study of lymphocyte development, function and signaling. We anticipate that our proposal to study this murine model carefully will contribute a significant amount of new information for understanding the diverse genetic and molecular bases of autoimmune diseases. The identification of new genes and new pathways may uncover new targets for the development of drugs to suppress the immune system in a specific way, instead of globally. The discovery of new disease genes may also be very useful in the management, care and diagnosis of the large number of patients with autoimmune diseases.